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DA-125, a novel anthracycline derivative showing high-affinity DNA binding and topoisomerase II inhibitory activities, exerts cytotoxicity via c-Jun N-terminal kinase pathway.

AbstractPURPOSE:
DA-125 [(8S,10S)-8-(3-Aminopropanoyloxyacetyl)-10-[(2,6-dideoxy-2-fluoro-alpha-L-talopyranosyl) oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacene-dione hydrochloride] is a novel anthracycline derivative with anticancer activity. In the present study, we compared the cytotoxicity of DA-125 with that of doxorubicin in H4IIE rat hepatoma cells and investigated the mechanistic basis. Because activation of MAP kinases, in particular c-Jun N-terminal kinase (JNK), is implicated in apoptotic cell death, the signaling pathways responsible for DA-125-induced apoptosis were studied.
METHODS:
Cytotoxicity and apoptosis were measured in H4IIE cells and cells were stably transfected with a dominant-negative mutant of JNK1 (JNK1-) by MTT and TUNEL assays. Inhibition of topoisomerase II activity was determined in vitro. Drug accumulation and DNA binding affinity were determined by fluorescence spectroscopy.
RESULTS:
The cytotoxicity of DA-125 was greater than that of doxorubicin (IC50 11.5 vs 70 microM). DA-125 induced apoptosis with 30-fold greater potency than doxorubicin. Inhibition of topoisomerase II by DA-125 was fourfold greater. The presence of excess beta-alanine, a DA-125 moiety, failed to alter cytotoxicity and accumulation of DA-125, indicating that the improved cytotoxicity of DA-125 did not result from the beta-alanine moiety. Greater cellular accumulation of DA-125 correlated with its high-affinity DNA binding. Although neither PD98059 nor SB203580 altered the degree of cytotoxicity induced by DA-125, JNK1 cells exhibited about a twofold greater viability than control cells. DA-125-induced apoptosis was also decreased in JNK1- -transfected cells.
CONCLUSIONS:
DA-125 potently inhibited topoisomerase II activity and induced apoptosis by a high rate of prooxidant production. DA-125 exhibited high-affinity DNA binding with improved cellular drug accumulation. Apoptosis induced by DA-125 involved the pathway of JNK1, but not ERK1/2 or p38 kinase.
AuthorsS G Kim, M Sung, K W Kang, S H Kim, M H Son, W B Kim
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 47 Issue 6 Pg. 511-8 (Jun 2001) ISSN: 0344-5704 [Print] Germany
PMID11459204 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • DNA, Neoplasm
  • Enzyme Inhibitors
  • Topoisomerase II Inhibitors
  • beta-Alanine
  • 7-O-(2,6-Dideoxy-2-fluoro-alpha-talopyranosyl)adriamycinone- 14-beta-alaniate hydrochloride
  • Doxorubicin
  • Peroxidase
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
Topics
  • Animals
  • Antineoplastic Agents (metabolism, pharmacology)
  • Carcinoma, Hepatocellular (drug therapy, metabolism)
  • DNA, Neoplasm (metabolism)
  • Doxorubicin (analogs & derivatives, metabolism, pharmacology)
  • Enzyme Inhibitors (pharmacology)
  • JNK Mitogen-Activated Protein Kinases
  • Liver Neoplasms (drug therapy, metabolism)
  • Mitogen-Activated Protein Kinases (metabolism)
  • Peroxidase (metabolism)
  • Rats
  • Topoisomerase II Inhibitors
  • Tumor Cells, Cultured
  • beta-Alanine (metabolism)

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